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The heart’s ability to adjust its contraction strength in response to increases in blood pressure can, when the condition becomes excessive, lead to arrhythmias and other serious heart conditions.

Ye Chen-lzu

Now, a multidisciplinary research team at UC Davis has found a key biological trigger — a protein known as nitric oxide synthase, or NOS — that makes the heart beat stronger in response to higher blood pressure, along with a way to turn that trigger off when it becomes overactive.

“The heart is a robust pump that can compensate for short-term increases in blood pressure due to changes in physical and emotional conditions — like exercise or joy,” said study senior author Ye Chen-Izu, assistant professor of pharmacology and biomedical engineering at UC Davis. “But there is a darker side to that compensating system that could lead to life-threatening heart diseases. Our work opens up new avenues for preventing that outcome.”

Chen-Izu pulled together an interdisciplinary team of biophysicists, chemists, engineers, physiologists and cardiologists for a study of the biological system that controls contractility of the heart under mechanical stress such as that caused by high blood pressure. They put heart muscle cells from mice into a “cell-in-gel” system that simulates mechanical stress on cells. The system, which was developed by Chen-Izu and Kit Lam, chair of the UC Davis Department of Biochemistry and Molecular Medicine, is transparent, allowing changes at the molecular level to be observed as they occur in living cells through high-power microscopes.

A series of experiments showed that as mechanical stress increases, the release of calcium increases and strengthens heart contractions so it can pump harder against higher blood pressure. They identified NOS as the molecule that initially senses mechanical stress and creates nitric oxide, which activates ryanodine receptors that increase the calcium release.

The researchers also discovered that an isoform of NOS — neuronal nitric oxide synthase, or nNOS — was responsible for spontaneous calcium sparks that occurred when cells were supposed to rest, likely due to the buildup of nitric oxide from ongoing mechanical stress.

“Under conditions of heavy, persistent mechanical load, the heart’s fine-tuned calcium control system becomes unstable, causing irregular heartbeats,” said Chen-Izu, whose research focuses on the biomechanics and bioelectricity of heart disease. “This could explain why high blood pressure can increase arrhythmias, which may lead to sudden cardiac death, heart failure and stroke.”

Additional experiments showed that a known nNOS inhibitor reduced calcium sparks while cells were responding to mechanical load, suggesting that the molecule is a key factor in instigating abnormal heart beats.

Watch a video of a mouse ventricular myocyte as it contracts in the cell-in-gel system, which allows researchers to observe what happens to heart cells during mechanical stress.

“Without our collaboration, we would not have invented the cell-in-gel system and never would have known that NOS is heavily involved in calcium regulation induced by mechanical stress,” Chen-Izu said.

Chen-Izu hopes to continue using the cell-in-gel system to study how cells respond to mechanical stress as it relates to hypertension-induced arrhythmias, muscular dystrophy-associated heart failure, and hypertrophic and dilated cardiomyopathies.

“This interdisciplinary approach opens up new avenues for finding treatments for numerous heart diseases with cellular stress at the core,” said Chen-Izu.

Additional researchers on the study were lead author Zhong Jian, Huilan Han, Tieqiao Zhang, Jose Puglisi, Leighton Izu, Ekama Onofiok, Jeffery Erickson, Yi-Je Chen, Balazs Horvath, Rafael Shimkunas, Wenwu Xiao, Yuanpei Li, Tingrui Pan, James Chan, Nipavan Chiamvimonvat, Donald Bers and Kit Lam from UC Davis; John Shaw of the University of Michigan; Tamas Banyasz of the University of Debrecen in Hungary; and Jil Tardiff of the University of Arizona.

The team’s work was funded by the National Institutes of Health (grant numbers R03-AG031944, R01-HL90880, R21-HL108300, R37-HL30077, R01-HL075274, R01-HL085844 and T32-HL86350), a U.S. Veteran’s Affairs Merit Review Grant, the Center for Biophotonics Science and Technology at UC Davis, a UC Proof of Concept Grant and UC Davis startup funds.

The study — "Mechanochemotransduction During Cardiomyocyte Contraction is Mediated by Localized Nitric Oxide Signaling" — is published in the March 18 issue of the journal Science Signaling and available at http://stke.sciencemag.org/

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